AHS is relatively rare, seen in only about 2% of patients initiating this immunosuppressive therapy [1, 2]. Adverse effects have been reported to occur between two and fourteen days after initiation of the medication [1,2,3,4,5,6]. Once a patient is sensitized, a re-challenge of the drug will typically have a rapid onset of the reaction, with previous case reports in the literature documenting onset within hours of re-exposure [1,2,3,4,5,6]. As supported by our case, the hypersensitivity reaction from re-exposure to azathioprine is often more severe, with hypotension and shock reported in up to one-third of cases [1,2,3,4,5,6]. The mainstay of treatment is supportive measures with fluid resuscitation and vasopressor/inotropic support if necessary. The hypersensitivity reaction typically resolves within days to weeks of cessation of the drug.

Azathioprine is metabolized to its active form 6-mercaptopurine (6-MP) and is subsequently inactivated by a methylation reaction catalyzed by thiopurine S-methyltransferase (TPMT). TMPT levels are commonly assessed prior to azathioprine initiation to prevent the side effects and toxicities that arise from azathioprine’s toxic metabolites (e.g. fevers, nausea/vomiting, granulocytopenia, and hepatocellular liver injury). Unlike the known mild to moderate toxicities of azathioprine that have been associated with low TPMT, azathioprine hypersensitivity has not been previously associated with TPMT levels.

Various rashes have been associated with AHS including erythema nodosum, small-vessel vasculitis, acute generalized exanthematous pustulosis (AGEP), nonspecific dermatitis, and Sweet syndrome. In the present case, the association of fever, neutrophilic dermatosis and of a severe systemic inflammatory response leading to shock and myocardial infarction (MI), could either be compatible with a diagnosis of drug-induced Sweet-like syndrome or Acute Generalised Exanthematous Pustulosis (AGEP), both of which having been previously described with azathioprine [1, 5]. Although systemic steroids are the mainstay of initial treatment in Sweet syndrome [7], they are not standard of care in AGEP [8]. Rather, in AGEP, resolution is typically noted within a short time frame after discontinuing the causative agent, and while topical steroids have been used to provide symptom relief, but the role of systemic steroids in AGEP is not well-established [8].

While the rash of neutrophilic dermatosis and distributive shock has been previously described in the setting of AHS, there have been no reports of azathioprine hypersensitivity and concurrent ACS. According to the 4th Universal Definition of Myocardial Infarction, the ACS in the case best fits the diagnosis of type II MI, which is defined as a “detection of a rise and/or fall of cardiac Troponin values with at least 1 value above the 99th percentile of the upper reference limit, and evidence of an imbalance between myocardial oxygen supply and demand unrelated to coronary atherothrombosis” with typical features of: symptoms of acute MI, new ischemic ECG changes, and/or imaging evidence of a new loss of viable myocardium or regional wall motion abnormalities in an ischemic territory. As such, in the absence of significant coronary atherosclerosis or coronary dissection, the ACS in the case was most likely a type II MI related to coronary vasospasm or oxygen supply-demand mismatch. Allergic acute coronary syndromes have previously been described in an entity known as Kounis syndrome, which is broadly defined as an ACS in the setting of a systemic allergic response, specifically related to vasospasm from inflammatory mediators in type I (IgE) hypersensitivity [9]. However, in the presented case, the mechanism of AHS is more related to massive systemic cytokine response relating to T cells and neutrophils, and therefore, does not quite meet previous definitions for Kounis syndrome. While inflammatory cytokines can play a role in atherothrombotic-related MI [10], this has not been well-established in non-atherothrombotic MI, as in the presented case. In the literature, little is known about ACS, including STEMI, in the context of cytokine release syndromes. While cytokine release syndromes have been recently postulated to be involved in COVID-19 infection-related acute coronary syndromes, the mechanisms are not well-established yet [11]. Further studies focused on the mechanisms of ACS in the setting of cytokine release syndromes, including azathioprine hypersensitivity, are required.